Dysregulated ipid homeostasis represents a major contributing factor in obesity-related chronic diseases, but the role of the central nervous system (CNS) in lipid metabolism during obesity is still poorly defined. Serotonin 2C receptors (5-HT2CRs) found in the CNS is predicted to regulate lipid homeostasis. For example, 5-HT2CR agonists have lipid-lowering benefits in human subjects, while atypical anti-psychotic drugs that inhibit 5-HT2CRs are associated with elevated serum cholesterol and triglycerides. However, it is still unclear which populations of 5-HT2CR-expressing neurons in the CNS mediate these effects on lipid homeostasis. Recent studies have found that 5-HT2CRs expressed by pro-opiomelanocortin (POMC) neurons in the hypothalamus directly regulate glucose homeostasis and insulin sensitivity independent of weight loss. The current proposal is to test whether 5-HT2CRs expressed by POMC neurons also have physiologically important effects on lipid homeostasis dissociable from body weight. This objective will be accomplished using genetically engineered mouse models and comprehensive analysis of lipid metabolism, including serum lipid profiles, white adipose tissue homeostasis, and the development of fatty liver disease. The first experimental aim will use mice lacking 5-HT2CRs only in POMC neurons to test whether the maintenance of normal lipid homeostasis requires 5-HT2CRs expressed by POMC neurons. The second experimental aim will use 5-HT2CR-null mice with re-expression of 5-HT2CRs only in POMC neurons to test whether 5-HT2CRs expressed only by POMC neurons are sufficient to rescue lipid homeostasis. Taken together, these approaches will provide mechanistic insight into the role of serotonin signaling in POMC neurons to regulate lipid homeostasis. The mouse models are relevant to human patients treated with atypical anti-psychotic drugs or obesity drugs that inhibit or activate 5-HT2CRs, respectively. These findings will advance the basic understanding of CNS pathways that control lipid metabolism during obesity and could potentially offer new lipid-lowering therapeutic targets.